The opening of the 21st century has been heralded as a turning point in biomedical research. The complete sequence and a dense map of the human genome, coupled with advanced genomics technologies holds the promise of dramatically accelerating the understanding of human disease, which in turn is expected to accelerate the pace of discovery of new therapeutics. Similarly, recent advances in synthetic organic chemistry have the potential to greatly improve chemical screening and compound optimization. In principle, these technical and conceptual advances have the potential to transform drug discovery. In practice, however, they have not yet done so. While emerging genomic and chemical technologies are available in isolation, they have not been creatively integrated into the drug discovery process. A key reason has been the lack of a concerted, interdisciplinary effort to merge the disciplines of genetics and chemistry into a new conceptual framework. We propose here an ambitious plan to create a new approach to drug discovery involving four components. Component A (U54 Leadership) which includes the IRC Steering Committee. Component B (Discovery Pipeline). This component aims to develop a drug discovery pipeline based on the paradigm of phenotypic screening. This includes developing i) systematic high-throughput screening of phenotypic assays for cellular states based on gene-expression and imaging;ii) expanded libraries of DOS compounds to facilitate high-throughput screening, target identification and medicinal chemistry optimization;and iii)genomics-based approaches to predictive toxicology. Component C (Target ID).This component aims to develop systematic approaches to identifying the protein target of a small molecule based on i) techniques for affinity capture and proteomic analysis;ii) novel approaches using RNA inhibition (RNAi);and iii) novel computational approaches to recognize distinctive cellular signatures. Component D (Driving Medical Projects). To drive its development and test its utility, the new paradigm must be applied to specific biomedical problems. This component will undertake six demonstration projects.